BLOOD PRESSURE

arterial blood pressure HYDRAULIC EQUATION ABP directly proportionate to CO and PVR

BP= CO x PVR Systolic BP Diastolic BP

cardiac contraction affected by cardiac output (CO) CO= volume of blood pumped by the left ventricle per contraction

blood filling of cardiac chambers affected by TPR/SVR/PVR -total peripheral resistance/ systemic vascular resistance/ peripheral vascular resistance TPR= resistance to passage of blood through precapillary arterioles

MAJOR FACTORS INFLUENCING BP Cardiovascular System

-both normotensive and hypertensive indls -hypertensive set at higher level Venous tone: degree of constriction; net capillary filtration, TPR, BP NORMAL REGULATION OF BLOOD PRESSURE

Hydraulic equation (BP= CO x TPR) -3 anatomic sites where CO and TPR are maintained (both normotensive and hypertensive): 1) arterioles (resistance vessels) 2) postcapillary venules (capacitance vessels) 3) heart 4) kidney contributes to maintenance of blood pressure by regulating the volume of intravascular fluid

Postural baroreflex - mediated by autonomic nerves

-responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture vasomotor area of the medulla

Carotid baroreceptors: stimulated by the stretch of the vessel

walls brought about by ABP

Baroreceptor activation inhibits central sympathetic discharge

Transition to upright posture baroreceptors sense the

reduction in arterial pressure as reduced wall stretch

sympathetic discharge is disinhibited increase in sympathetic

outflow PVR (constriction of arterioles) and CO (direct

stimulation of the heart and constriction of capacitance vessels,

which increases venous return to the heart) normal BP

RAAS - humoral mechanism Vasoactive substances

- local release from vascular endothelium may also be involved in the regulation of vascular resistance

- endothelin-1 constricts BVs -nitric oxide dilates blood BVs

*Baroreflex + humoral mech (RAAS) = contribute to maintain normal BP at the 4 anatomic sites

* Hypertensive px differs in that the baroreceptors and the renal

blood volume-pressure control systems appear to be "set" at a

higher level of blood pressure.

Physiology

Blood flow: volume of blood that flows through any tissue in a given time period (in mL/min) Cardiac output: volume of blood that circulates through systemic (or pulmonary) blood vessels each minute; SV x HR Stroke volume: volume of blood pumped by the ventricles per contraction Vascular Resistance: opposition to blood flow bet. Blood and the walls of the bvs Venous return: volume of blood flowing back to the heart through systemic veins; due to pressure generated by contraction of left ventricle Determinants of arterial pressure: cardiac output- determined by SV and HR vascular resistance- determined by functional and anatomic changes in small arteries Cardiac Output Stroke volume Preload: degree of stretching of heart muscles -proportional to EDV high heart rate, short vent. diastole, low EDV, low SV -high venous return, high EDV high SV, high CO, high BP

Myocardial contractility: positive inotropic agents (ANS stimulation; E/NE; increased Ca2+; digitalis); negative inotropic agents (inhibition of ANS; anoxia, acidosis, increased K+) Afterload: higher pressure, lower stroke volume, low CO lower BP

Heart Rate Autonomic Regulation -CV center in medulla increase/decrease frequency of nerve impulses in sympathetic and parasympathetic branches of ANS -proprioceptors; chemoreceptors; baroreceptors

Chemical regulation -Hormones E/NE increase both heart rate and contractility

-Cations Elevated blood levels of K+ or Na+ decrease heart rate and contractility; Excess Na_ blocks Ca2+ inflow during cardiac action potentials, thereby decreasing the force of contraction; whereas excess K+ blocks generation of action potentials; moderate increase in interstitial Ca2+ level speeds heart rate and strengthens the heartbeat Age, gender, physical fitness, and body temperature

Vascular Resistance size of the lumen- smaller lumen greater resistance to blood flow BP increases (vasoconstriction) blood viscosity- depends on ratio of RBCs to plasma volume (polycythemia, dehydration); higher viscosity higher resistance higher BP -anemia, hemorrhage low viscosity low BP total blood vessel length: longer bv, higher resistance; obese have addl bvs in their adipose tissues higher bv length higher BP Venous Return skeletal muscle pump: contraction, pushes blood upward more blood returned to heart higher BP respiratory pump: inhalation, blood pushed upward more blood returned higher BP

Total Blood Volume Renin-angiotensin-aldosterone system

Decrease in blood volume decreased blood pressure juxtaglomerular cells secrete renin converts angiotensinogen, a plasma protein produced by the liver, into angiotensin I (lungs) the enzyme ACE converts angiotensin I into the hormone angiotensin II Blood level of angiotensin II increases Ang II stimulates the adrenal cortex to secrete aldosterone ( kidneys) aldosterone increases reabsorption of Na and water so that less is lost in the urine; Ald also stimulates the kidneys to increase secretion of K+ and H+ into the urine increased water reabsorption by the kidneys, blood volume increases blood pressure increases to normal --Ang II vasoconstriction of the arterioles increases blood pressure raise blood pressure to normal

HYPERTENSION Most common CV disease Increasing prevalence with advanced age Other factors: psychological stress, environmental and dietary factors ( salt and potassium or calcium intake) as contributing to the development of HTN Elevated arterial pressure, pathological changes in vasculature and hypertrophy of LV Principal cause of stroke Major risk factor for CAD and its attendant complications, MI and sudden cardiac death Major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of the aorta ETIOLOGY OF HYPERTENSION Primary/ Essential/Idiopathic HTN

- Familial and is likely to be the consequence of an interaction between environmental and genetic factors -With unknown cause (~90%)

Secondary HTN

-With known cause (~10-15%)

-e.g. renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing's disease, and primary aldosteronism

GESTATIONAL HYPERTENSION during pregnancy predisposes a patient to pre- eclampsia and eclampsia -Preeclampsia abnormal condition of pregnancy characterized by sudden hypertension (140/90mmHg), proteinuria (300mg/24hr) and generalized edema that typically appears after the 20th week of pregnancy -Other signs and symptoms are generalized edema, blurred vision, and headaches -Preeclampsia might be related to an autoimmune or allergic reaction resulting from the presence of a fetus (1st pregnancy) -Eclampsia: more life threatening (with seizures) Drugs: methyldopa (DOC) hydralazine labetalol

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Classification of Blood Pressure for Adults (Age >18)a JNC 7 (7th report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure) -based on the average of two or more properly measured, seated BP readings on each of two or more office visits -if SBP and DBP values yield different classifications, the highest category is used for the purpose of determining a classification

BP Classification

SBP mmHg

DBP mmHg

Lifestyle Modification

Initial Drug Therapy

W/o compelling indication

With compelling indication

Normal 100 Yes Two-drug combinationc for most (thiazide and ACEI/ARB/BB/CCB)

b for px w/ DM of CKD, values > 130/80mmHg are considered above goal

c initial combined therapy should be used cautiously in those at risk for orthostatic hypotension d Tx px w/ CKD or DM to BP goal of 130/80 mmHg

COMPELLING INDICATIONS are co-morbid conditions where specific drug therapies have been shown in outcome trials to provide unique long-term benefits

* A diagnosis cannot be made based on one elevated BP measurement. An elevated value from the average of two or more measurements on two or more clinical encounters is needed to diagnose hypertension.

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Hypertensive Crises 180/120 mm Hg 2 categories: Hypertensive emergencies Hypertensive urgencies

with acute target-organ damage immediate treatment with IV drugs goal: DBP < 110

without damage managed with oral drugs for hours or days

Overall Goal of Therapy to reduce hypertension-related morbidity & mortality goal BP values based on JNC 7: most patients:

A. DIURETICS

B. SYMPATHOPLEGICS I. Centrally-acting Sympathoplegics sympathetic outflow from vasopressor centers in the brainstem but retain or increase sensitivity to baroreceptor control Antihypertensive and toxic actions are generally less dependent on posture

Drug Properties Pharmacologic Effect/ Mechanism

of Action

Dosage/Administration/ Pharmacodynamics

Side effects

Methyldopa (Aldomet)

PRODRUG Analog of L-dopa; converted to - methyldopamine and - methylnorepinephrine

Agonist at presynaptic a2receptors in the brainstem REDUCES TPR inhibits dopaminergic mechanism in the hypothalamus prolactin lactation

Maximal anti HTN effect in 46 hours Persists for up to 24 hours SAFE FOR PREGNANT WOMEN

overt sedation at onset of tx chronic use: persistent

mental lassitude (slow) and impaired mental concentration

lactation positive Coombs test -presence of antigens in the

RBC hemolytic anemia

Clonidine (Catapres) 75mcg / 150mcg

Lipid-soluble and rapidly enters the brain from the circulation 2-imidazoline derivative (originally tested as nasal decongestant)

Agonist at a2-receptors Partial agonist at a- receptors inhibits pressor effects of other a-agonists Direct stimulation of a-adrenoceptors in arterioles sympathetic and parasympathetic tone BP , TPR and bradycardia renal vascular resistance Produces a brief rise in blood pressure followed by more prolonged hypotension (IV)

Relatively short half-life Effect is directly related to blood concentration = PO bid (or as a patch) to maintain smooth blood pressure control Transdermal: reduces blood pressure for 7 days after a single application Increasing doses are more effective (but also more toxic) Tapering of dose with simultaneous administration of alternative anti-HTN drug

WITHDRAWAL-INDUCED REBOUND HYPERTENSION Tx: phentolamine+propranolol Dry mouth and sedation --> centrally-acting and dose-dependent coincide temporally w/ the drugs anti-HTN effect Hypertensive crisis (>1mg/day) nervousness, tachycardia, headache, sweating after omitting 1 or 2 doses

TX: reinstitute clonidine OR admin of mixed /-adrenoceptor-blockers

CI: mental depression DI: Tricyclic antidepressants (TCAs) a-adrenoceptor-blocking action

Guanfacine (Tenex) Guanabenz (Wytensin)

adjunct drugs avoided unless unresponsive to other meds

share the central adrenoceptor-stimulating effects of clonidine do not appear to offer any advantages over clonidine

II.Peripherally-acting sympathoplegics Trimethaphan Ganglionic receptor

blocker -competitively blocks nicotinic cholinoceptors on postganglionic

IV infusion for hypertensive emergencies

adverse effects of ganglion blockers: -sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) -parasympathoplegia

neurons in both sympathetic and parasympathetic ganglia

(constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth)

Reserpine Alkaloid from Rauwolfia serpentina

Inhibits catecholamine storage by blocking the ability of aminergic transmitter vesicles to take up and store biogenic amines (VMAT) Parkinsonism dopamine depletion in the corpus striatum

CNS: sedation, mental depression, and parkinsonism symptoms readily enters the brain GI: mild diarrhea, GI cramps and increased gastric acid secretion CI: peptic ulcer, mental depression

Guanethidine Very polar drug Inhibits NE release at nerve endings

-concentrated in transmitter vesicles where it replaces norepinephrine causes a gradual depletion of norepinephrine stores in the nerve ending

Long half-life (5 days) Gradual onset of sympathoplegia (maximal effect in 12 weeks) and persists for a comparable period after cessation of therapy

Profound sympathoplegia Marked postural hypotension, diarrhea, and impaired Ejaculation No CNS effects vs. other anti-HTN drugs too polar! Diarrhea parasympathetic dominance DI: cocaine, amphetamine, TCS, phenothiazines, phenoxybenzamine (block CA uptake or displaces amines) -nasal decongestant CI: pheochromocytoma

Guanadrel guanethidine-like drug

Orthostatic hypotension Impaired sexual function in males

III. Alpha-1 blockers reduce arteriolar resistance increase venous capacitance cause vasodilation

Prazosin (Minipress) Terazosin (Hytrin) Doxazosin (Cardura)

essential hypertension CHF BPH

FIRST-DOSE PHENOMENON (highest in prazosin) -sudden fall in BP when abruptly changing from lying to standing position Postural hypotension related to first dose or when drug is resumed after several months off Syncope in 1% with prazosin > 2 mg Self-limiting Best started on a low dose and taken at night (hs)

Nonselective Alpha-Adrenoceptor Receptor Blockers

Phentolamine Phenoxybenzamine

Diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines

IV. Beta-blockers

competitive inhibitors of catecholamines at beta-adrenoreceptor sites (B1, B2, B3)

B2- bronchial & peripheral BVs (brocho & vasodilation) B3- adipose tissues (CA-induced thermogenesis, cardiac

contractility) act to reduce the effect of the catecholamine agonist on

sensitive tissues heart contractility heart rate cardiac output renin secretion Cardiac Effects

Decrease contractility negative inotropy)

mask hypoglycemia CI: COPD, bronchial asthma SI: withdrawal syndrome severe bradycardia and heartblock Cardioselectivity: ability of a drug to preferentially bind to one type of B-receptor Tx for angina but higher doses lowers cardioselectivity

Decrease relaxation rate (negative lusitropy) Decrease heart rate (negative chronotropy) Decrease conduction velocity (negative dromotropy)

Vascular Effects Smooth muscle contraction (mild vasoconstriction)

Nonselective

Propranolol (Inderal) Nadolol (Corgard)

Timolol (Blocadren) Pindolol (Visken)

Selective Betaxolol (Betaoptic)

Bisoprolol (Zebeta) Esmolol (Brevibloc) Acebutolol (Sectral) Atenolol (Tenormin)

Metoprolol (Lopressor)

Mixed a-& -blockers Labetalol (Normodyne)

Carvedilol (Coreg)

With intrinsic sympathomimetic activity (ISA) Acebutolol

Pindolol Penbutolol

With membrane-stabilizing activity Pindolol

Acebutolol

For chronic open-angle glaucoma Carteolol (Ocupress) Betaxolol (Betaoptic)

Levobunolol (Betagan) Metipranolol (Optipranolol)

Timolol (Timoptic) Levobetaxolol (Betaxon)

Class/Drug HTN Angina Arrhy MI CHF Comments

Non-selective B1/B2

Carteolol X ISA; long-acting; also for glaucoma

Carvedilol X x a-blocking acitivity

Labetalol X X ISA; a-blocking acitivity

Nadolol X X X X long-acting

Penbutolol X X ISA

Pindolol X X ISA; MSA

Propranolol X X X X MSA; prototype

Sotalol X Several other significant mech

Timolol X X X X Primarily for glaucoma

B1 selective

Acebutolol X X X ISA

Atenolol X X X X

Betaxolol X X X MSA

Bisoprolol X X X

Esmolol X X Ultra short acting; intra/ postoperative HTN

Metoprolol X x X x X MSA Nebivolol x Rel. selective in most pxl vasodilationg (NO rel)

C. VASODILATORS relax smooth muscles of blood vessels TPR and mean ABP compensatory responses mediated by baroreceptors and the sympathetic nervous system, as well as renin, angiotensin, and aldosterone because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction (kaya dapat polypharmacy)

Oral (long-term outpx therapy)

Parenteral (hypertensive emergencies)

Calcium channel blockers (both)

Hydralazine Minoxidil

Sodium nitroprusside Diazoxide

Fenoldopam

Drug Indication Pharmacologic Effect/

Mechanism of Action

Dosage/Administration/ Pharmacodynamics

Side effects

Hydralazine (Apresoline)

Treatment of gestational HTN Combination of hydralazine with nitrates is effective in heart failure

Direct relaxation of arteriolar (but not veins) smooth muscle = SVR

Well absorbed Rapid first-pass metabolism (~25% bioavailability) rapid acetylators have first-pass metabolism, blood levels, and antiHTN benefit from a given dose than do slow acetylators t1/2 = 1.5-3 h bid-tid for smooth BP control SLE-like syndrome (=400mg/day)

SLE-like effects: myalgia, arthralgia, rashes, fever (> 400mg/d) not assoc. w/ renal damage; reversible IHD: reflex tachycardia & sympathetic stimulation angina tachyphylaxis to its antihypertensive effects developed rapidly Toxicity: headache, nausea, anorexia, palpitations, sweating, and flushing

Minoxidil (Loniten) Topical: Rogaine stimulant to hair

growth for correction of baldness

PRODRUG AM: Minoxidil sulfate Very efficacious orally active vasodilator Must be used in combination with a a-blocker and a loop diuretic Should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine

Opening of K+ channels in smooth muscle membranes by minoxidil sulfate stabilizes membrane at resting potential no contraction Dilates arterioles but not veins

t1/2 = 4h 90% bioavailability 40 mg/d

Associated with reflex sympathetic stimulation and sodium and fluid retention (compensatory mechanism) Hypertrichosis, headache, sweating

Sodium nitroprusside (Nitropress) Complex of iron, cyanide(CN) groups, and a nitroso moiety Na2[Fe(CN)5NO)]

Useful in hypertensive emergencies and severe HF Rapidly lowers BP; effects disappear within 1-10 mins after discontinuation

Activation of guanylyl cyclase (either via release of NO or by direct stimulation of the enzyme) intracellular cGMP relaxation of vascular smooth muscle Dilates BOTH arteries & veins = PVR, venous return

Parenterally administered (IV infusion) Freshly prepared, covered w/ opaque foil (light sensitive) Begins at 0.5 mcg/kg /min and may be increased up to 10 mcg/kg/min as necessary Rapidly metabolized by uptake into RBCs w/ liberation of CN CN metabolized by mitochondrial enzyme, rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate CN- + sulfur (rhodanase) SCN-

CN toxicity: metabolic acidosis, arrhythmias, excessive hypotension, death Low dose toxicity: defect in CN metabolism ANTIDOTE: Sodium thiosulfate (sulfur donor) and hydroxocobalamin (combine w/ CN0 to form cyanocobalamin/B12 Accumulation of thiocyanate in renal insufficiency SCN- toxicity: weakness, disorientation, psychosis, muscle spasms, and convulsions (> 10 mg/dL)

Thiocyanate is distributed in ECF Slowly eliminated by the kidney

Delayed hypothyroidism - inhibition of I- uptake by the thyroid (rare)

Diazoxide (Hyperstat IV)

Long-acting arteriolar dilator Occasionally used to treat HTN emergencies PO Proglycem: used to manage hypoglycemia secondary to insulinoma

Prevents vascular smooth muscle contractions by opening K+ channels and stabilizing membrane potential at resting level Inhibits insulin release from the pancreas (probably by opening K+ channels in the -cell membrane)

Dose gradually increase (50 150mg) Effect post rapid injection (within 5 mins) and lasts for 4-12 h Bound extensively to serum albumin and to vascular tissue reduce dose in renal px Partially metabolized

Rapid fall in TPR and mean ABP associated with substantial tachycardia and increased CO hypotensive effects when patients are pretreated with a-blockers to prevent the reflex tachycardia and associated increase in CO

Fenoldopam (Corlopam)

Peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension

Agonist of dopamine D1 receptors dilation of peripheral arteries + natriuresis

Rapidly metabolized by conjugation t1/2 = 10 minutes Administered by continuous IV infusion Initiated at a low dosage (0.1 mcg/kg/ min) titrated upward every 15 or 20 minutes to a maximum dose of 1.6 mcg/kg/min

Reflex tachycardia, headache, and flushing; increased IOP (CI: glaucoma)

Calcium Channel Blockers Anti-anginal & anti-arrhythmic effects Reduce PVR and BP by inhibiting Ca+2influx into arterial smooth muscle cells

Pharmacologic Effects peripheral edema reflex tachycardia (DHP) bradycardia (Non-DHP) heart block (Non-DHP + Beta Blocker)

Dihydropyridine type block Ca+2channel in blood vessels

- cardiac depressant effect, more selective vs non-DHP

Non-dihydropyridine type -depresses both heart and BVs

Amlodipine (Norvasc) Felodipine (Plendil)

Isradipine (DynaCirc) Nicardipine (Cardene)

Nifedipine (Adalat) Nisoldipine (Sular)

Verapamil (Isoptin) Greatest depressant effect on heart HR and CO

Diltiazem (Cardizem) Intermediate actions block Ca+2channels in heart & blood vessels

D. Angiotensin Antagonists ACE inhibitors Angiotensin II Receptor blockers

ACE inhibitors Angiotensin II Receptor blockers Inhibit Angiotensin Converting Enzyme (ACE), thereby preventing the conversion of Angiotensin I (decapeptide) into the active Angiotensin II (octapeptide) ACE inhibits:

Peptidyl dipeptidase converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II

Plasma kininase: inactivates bradykinin (potent vasodilator) w/c works by stimulating release of nitric oxide and prostacyclin

Angiotensin II Receptor Blockers provide similar benefits as with ACEIs less occurrence of angioedema & dry cough

ACE Inhibitors

BP principally by TPR CO and HR are not significantly changed

Do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease vs vasodilators -absence of reflex tachycardia may be due to downward resetting of the baroreceptors or to enhanced parasympathetic activity

Drug Indication Mechanism of Action

Dosage/Administration/ Pharmacodynamics

Side effects

Captopril (Capoten) CKD: diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure) Probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure HF and MI Reduce incidence of diabetes in patients with high cardiovascular risk

Inhibit peptidyl dipeptidase & plasma kininase

Short-acting BID/TID

Idiosyncratic dry cough (accompanied by wheezing) Angioedema Hyperkalemia more likely in px assoc. w/ DM or renal insufficiency Cough + Angioedema due to bradykinin and substance P DI: potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia CI: second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death

Enalapril (Vasotec) IV only

oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril

Peak concn of enalaprilat occurs after 3-4 hrs BID/TID

Lisinopril (Prinivil) lysine derivative of enalaprilat

1080 mg once daily

Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Benazepril, fosinopril, moexipril trandolapril

All are prodrugs Converted to the active agents by hydrolysis, primarily in the liver All ACEIs except fosinopril and moexipril are eliminated via the kidney (lower dose)

Angiotensin II Receptor blockers

Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar) Telmisartan (Micardis) Valdesartan (Diovan)

no effect on bradykinin metabolism more selective blockers of angiotensin effects than ACE inhibitors have the potential for more complete inhibition of angiotensin action vs ACEIs because there are enzymes other than ACE that are capable of generating angiotensin II provide benefits similar to those of ACEIs in px w/ HF or CKD SI: similar to ACEIs including the hazard of use during pregnancy Cough and angioedema can less common

Aliskiren

Selective rennin inhibitor Directly inhibits renin(acts earlier in RAAS vs. ACEIs or ARBs)

Same effectiveness in lowering BP as ACEIs, ARBs, and thiazides Metabolized by CYP 3A4 Available as a FDC (fixed dose concn.) with valsartanas well as HCTZ

SE: diarrhea (higher doses), cough and angioedema (less than ACEIs) CI in pregnancy Hyperkalemia significantly more common with aliskiren+valsartan